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Design and Synthesis of 4-Substituted Benzamides as Potent, Selective, and Orally Bioavailable IKs Blockers

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journal contribution
posted on 17.10.2001, 00:00 authored by John Lloyd, Joan B. Schmidt, George Rovnyak, Saleem Ahmad, Karnail S. Atwal, Sharon N. Bisaha, Lidia M. Doweyko, Philip D. Stein, Sarah C. Traeger, Arvind Mathur, Mary Lee Conder, John DiMarco, Timothy W. Harper, Tonya Jenkins-West, Paul C. Levesque, Diane E. Normandin, Anita D. Russell, Randolph P. Serafino, Mark A. Smith, Nicholas J. Lodge
Multiple delayed rectifier potassium currents, including IKs, are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent IKs blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.